3. Electronic Theses and Dissertations (ETDs) - All submissions
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Item Clinical and immunological epidemiology of group B streptococcus (GBS)(2016-02-22) Dangor, ZiyaadIntroduction: Group B Streptococcus (GBS) is a leading cause of neonatal sepsis and meningitis. Vaccinating pregnant women against GBS may protect their infants from invasive GBS disease. The licensure of GBS vaccines might be based on immunological parameters should correlates of protection be established. We evaluated the burden of invasive GBS disease, and explored the association between naturally occurring GBS antibody concentrations and invasive GBS disease in South African infants. Methods: Using a case-control study, we compared maternal and infant GBS serotypespecific capsular and surface-protein IgG antibody concentrations. Neurodevelopmental screening was performed at 3 and 6 months-of-age. Furthermore, we compared the effect of maternal HIV-infection on GBS specific antibody concentrations and transplacental antibody transfer. Results: The incidence (per 1,000 live births) of invasive GBS disease within 6 days of life was similar between HIV-exposed (1.13) and HIV-unexposed infants (1.46; p=0.487). However, there was a 4.67-fold (95% CI: 2.24-9.74) greater risk of invasive GBS disease at age 7-90 days in HIV-exposed infants (2.27 vs. 0.49; p<0.001). The overall case fatality ratio among cases was 18.0%, and the adjusted odds of developing neurological sequelae at 6 months age was 13.2-fold (95% CI: 1.4-121) greater in cases (13.2%) than controls (0.4%). Median antibody concentrations (μg/mL) were lower in HIV-infected than HIV-uninfected women for serotypes Ib (p=0.033) and V (p=0.040); and for pilus island (PI)-1 (p=0.016), PI-2a (p=0.015), PI-2b (p=0.015) and fibrinogen-binding protein A (p<0.001). For serotypes Ia and III, cord to maternal ratios were 37.4% (p<0.001) and 32.5% (p=0.027) lower in HIV-infected compared to HIV-uninfected mother-newborn dyads. Using Bayesian modelling, we demonstrated >90% reduction in risk of invasive GBS disease with maternal antibody concentrations ≥6 μg/mL and ≥3 μg/mL for serotype Ia and III, respectively. There was no association between GBS surface-protein antibody concentrations and invasive GBS disease. Conclusion: The high burden of invasive GBS disease in South Africa is partly due to the high prevalence of maternal HIV-infection (29%), which is associated with lower GBS antibody concentrations and transplacental antibody transfer. We identified putative correlates of protection for GBS serotype-specific capsular antibodies to serotypes Ia and III, which could facilitate vaccine licensure.Item A time-series analysis on the impact of the antiretroviral treatment program on the burden of hospitalization for culture-confirmed Mycobacterium tuberculosis in Sowetan children(2013-10-15) Dangor, ZiyaadIntroduction: Highly active antiretroviral treatment (HAART) programs in heavily HIV-TB burdened countries may reduce the risk of TB in children directly by improving the immune system of HIV-infected children; and indirectly by reducing the force of transmission from the adult population. The incidence of childhood TB is a sentinel measure of the control of infectious adult TB cases in the community. Objective: We evaluated the impact that scaling-up of the HAART program in Soweto had on the incidence of hospitalization for culture-confirmed TB in children. Methods: The study was undertaken in Soweto, where the prevalence of HIV was 4-5% in children between 2005 and 2009. The estimated HAART coverage increased from 43% in 2005 to 84% by 2009 in children with HIV/AIDS. Hospitalized cases of culture-confirmed TB in children 3 months to 14 years of age were identified through laboratory and clinical electronic databases. Results: Overall, the incidence (per 100 000) of hospitalization for culture-confirmed TB declined by 58% (95%CI 49.3-65.2) from 2005 (71.4) compared to 2008-9 (30.0); p<0.0001. This included a 67% (95%CI 58.5-74.8) reduction in incidence among HIV-infected children from 2005 (1 601) compared to 2008-9 (517; p<0.0001). v In addition, a 33% reduction was observed in HIV-uninfected children (incidence 19.3 vs 12.9; p=0.016). Fifty-six percent of TB episodes, across all study periods, occurred in HIV-infected children who were mainly (76%) severely immunocompromised. Conclusions: Up-scaling of the HAART program in South Africa has been associated with decline in the incidence of culture-confirmed TB, more so in HIV-infected than HIV-uninfected children. Severely immunocompromised HIV-infected children, however, need to be identified and targeted with HAART and other strategies to further reduce the burden of TB in this group.